To our knowledge, this is the largest reported study to assess cardiovascular involvement in patients with duplication 17p11.2 syndrome. We identified cardiovascular abnormalities in 10 of 25 (40%) patients with duplication 17p11.2 syndrome. This ratio is higher than in the general population, even though ASD (0.66%),14
and PFO (10–20%)14
are relatively common CHDs. Nine of our 10 subjects had a structural abnormality; one had only an ECG abnormality. The most frequent abnormality was dilation of the aortic root with varying degrees of severity. Hypoplastic left heart was reported in two duplication 17p11.2 syndrome patients,6,8
one of whom was evaluated at our institution after cardiac transplantation and was not included in this report because we did not perform his cardiac evaluation.6
Interestingly, only 6 of the 16 subjects (37.5%) with common duplications had a cardiovascular abnormality, although they all had the same 3.7 Mb genomic duplication (). On the other hand, the individual with the largest duplication (2711) had a normal cardiac evaluation. These findings demonstrate incomplete penetrance of CHDs in patients with duplication 17p11.2 syndrome. Incomplete penetrance is observed for other phenotypic aspects of SMS deletion 17p11.2 syndrome16,17
and other genomic disorders.18
Intriguingly, CHD is observed in 57% (4/7) of all nonrecurrent duplication subjects and 66.7% (4/6) of the patients with nonrecurrent duplications larger than 3.7 Mb, whereas a lower observation ratio of 37.5% is observed in patients with the 3.7 Mb common duplication. This correlation indicates that there are potentially multiple genes or genetic factors in 17p11.2 that contribute to the cardiovascular phenotype in duplication 17p11.2 syndrome and that some of them may map outside of the 3.7 Mb common duplication interval.
We recognize that ASD, VSD, and PFO are relatively common congenital heart lesions. However, our findings of aortopathy are interesting and may be suggestive of connective tissue disease involvement. This could have clinical implications for patients with aortic and/or mitral valve disease, such as the one patient we identified with an abnormal mitral valve and prolapse of the anterior leaflet. Furthermore, aortic involvement was not confined to the root, suggesting that a more diffuse vasculopathy should be considered in these patients. This would have important diagnostic implications, as a more advanced imaging technique such as computed tomography angiography or magnetic resonance angiography may be indicated for comprehensive aortic assessment. In addition, evidence of aortopathy by noninvasive imaging analysis may necessitate appropriate medical therapy, and if severe dilation of the aorta was found (as in 2211), surgical intervention may be discussed secondary to the risk of possible dissection. Given the small number of patients in our cohort and limited clinical follow-up, the exact implications of aortic involvement, and medical and/or surgical interventions cannot be determined. Our study is meant to characterize the spectrum of disease, which includes vascular involvement. Because these clinical delineation studies represent the initial characterizations of a relatively newly defined condition, and our study is not longitudinal in nature, no clear clinical management inferences can be made regarding the potential severity of this finding. However, given the findings of aortopathy in multiple patients, future longitudinal studies are warranted.
Our study provides important insight into the long-term management of patients with duplication 17p11.2 syndrome. First, given the potential need for medical and surgical intervention, patients with duplication 17p11.2 syndrome should be referred to a qualified cardiovascular specialist. Given our findings of structural heart disease, a baseline echocardiogram and ECG should be obtained at the time of diagnosis. One subject had isolated premature atrial complexes with no evidence of structural heart disease. The authors recognize that the importance of these ECG findings is unknown, given the lack of follow-up and ambulatory monitoring. Findings of premature atrial complexes on ECG are common in the general healthy population, but the significance of these irregular beats in the duplication 17p11.2 population is unclear. However, in light of the important clinical manifestations of aortopathy documented herein, appropriate serial imaging studies are necessary to delineate the vascular structures. Because transthoracic echocardiography provides limited visualization of the proximal aorta, more advanced imaging techniques such as computed tomography angiography or magnetic resonance angiography may be needed to further define the thoracic aorta, as well as the abdominal aorta and primary branch vessels.
There are limitations to our study. The patient population was small, and not all patients had follow-up echocardiograms to assess the progression of aortic or valvular disease. Limited data were available on the clinical course, including symptoms and medical therapies. Because no ambulatory electrocardiographic monitoring was performed in these patients, the occurrence of arrhythmia may have been underestimated.
In conclusion, duplication 17p11.2 syndrome is associated with structural heart disease, aortopathy, and electrocardiographic abnormalities. Patients should have thorough cardiac evaluation at diagnosis and should be monitored over time for the development of cardiovascular involvement. In addition, referral to a cardiologist for further management is indicated in patients with cardiovascular disease. Studies of the progression of cardiovascular disease in these patients may lead to the development of guidelines for patient care.